Synergy between a collagen IV mimetic peptide and a somatotropin-domain derived peptide as angiogenesis and lymphangiogenesis inhibitors

Abstract

Angiogenesis is central to many physiological and pathological processes. Here we show two potent bioinformatically-identified peptides, one derived from collagen IV and translationally optimized, and one from a somatotropin domain-containing protein, synergize in angiogenesis and lymphangiogenesis assays including cell adhesion, migration and in vivo Matrigel plugs. Peptide-peptide combination therapies have recently been applied to diseases such as human immunodeficiency virus (HIV), but remain uncommon thus far in cancer, age-related macular degeneration and other angiogenesis-dependent diseases. Previous work from our group has shown that the collagen IV-derived peptide primarily binds β1 integrins, while the receptor for the somatotropin-derived peptide remains unknown. We investigate these peptides’ mechanisms of action and find both peptides affect the vascular endothelial growth factor (VEGF) pathway as well as focal adhesion kinase (FAK) by changes in phosphorylation level and total protein content. Blocking of FAK both through binding of β1 integrins and through inhibition of VEGFR2 accounts for the synergy we observe. Since resistance through activation of multiple signaling pathways is a central problem of anti-angiogenic therapies in diseases such as cancer, we suggest that peptide combinations such as these are an approach that should be considered as a means to sustain anti-angiogenic and anti-lymphangiogenic therapy and improve efficacy of treatment.

Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling

“…After polymerization of the Matrigel at 37°C for 1 h, human umbilical vein endothelial cells (HUVECs) (Gibco-BRL, Invitrogen Corporation, Carlsbad, CA, USA) starved of serum for 2 h were harvested by using trypsin/EDTA, washed with assay medium, and seeded at a density of 7.5 × 10 3 cells per well (final volume 500 μl) on the polymerized Matrigel in the presence or absence of 30 ng/ml VEGF along with TAM, CXB, or both [29,30]. Plate was incubated at 37°C, 5% CO 2 for 24 h, then the medium was aspirated and cells were fixed in 10% neutral buffered formalin.…”

Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment

“…Specifically in breast cancer, tumour LV are the predominant routes of tumour dissemination. Thus current interest in the application of anti-angiogenic agents as cancer therapeutics has led to strategies combining inhibitors of angiogenesis and lymphangiogenesis with the goal of developing more effective anti-cancer therapies (Refs 62, 105, 149, 150). …”

Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

“…Among them, peptides derived from collagen type IV potently inhibited angiogenesis in vivo and in vitro [7, 8]. In this study, we evaluated the in vivo efficacy of SP2024, a new variant of these biomimetic peptides that has been shown to interfere with integrin β1 interactions as well as vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways in endothelial cells [9]. …”